Molecular and Translational Imaging Core

Full service preclinical and clinical imaging:  The two MTIC sites perform a range of small animal imaging procedures, with the Evanston site offering MRI (9.4T and 7T), PET and SPECT/CT, bioluminescence, fluorescence and near IR imaging; and the Chicago campus offering MRI, PET/CT, and X-ray Digital Subtraction Angiography (used for interventional procedures). Each site is directly accessible from a vivarium, with the Evanston site having a dedicated in-house vivarium (managed by the Center for Comparative Medicine) that is fully equipped for small animal surgery, anesthesia, and monitoring.  Clinical studies can be performed at the Chicago site, which is equipped with 1.5 and 3T MRI clinical scanners and a clinical scanner capable of simultaneous PET and MR imaging.

Data analysis, image processing and visualization: MTIC provides workstations equipped with advanced imaging analysis software (e.g., VivoQuant, Amira, JIM, custom code written in MATLAB, etc.) appropriate for the type of imaging being performed and assistance in the use of this software. MTIC also offers technical and computational support to all users for the development of customized image processing pipelines. The Evanston facility showcases one of the most advanced 3-D visualization displays in the world, with a wall consisting of a 5x5 array of 46" HD LCD display tiles for the display and manipulation of images.

Consultation and Study Planning: MTIC staff provide consultation on 1) project-specific scientific and technical issues, 2) selection of appropriate imaging modalities, 3) use of imaging probes, 4) sensitivity of approaches, 5) analysis of imaging data, and 6) potential new imaging approaches. MTIC also assists users in preparing grant applications and manuscripts.

User Training and Education: Part of MTIC’s educational mission is to train new users to obtain and analyze imaging data. Training protocols are in place for all instrumentation (IVIS, MRI, PET/SPECT/CT). MTIC participates in a Biomedical Engineering course on magnetic resonance imaging (BME327) and is responsible for several lectures in an advanced organic chemistry course (CHEM415). During the current funding period, MTIC hosted > 35 outreach events, many of which utilized the 3-D visualization display.

Evanston

• Bruker 7 T Pharmascan - Small Animal MRI (mouse, rat)
• Bruker 9.4 T Biospec - Small Animal MRI (mouse, rat, rabbit)
• Mediso NanoScan PET/CT - Small Animal PET/CT (mouse, rat)
• MILABS SPECT/CT - Small Animal SPECT/CT (mouse, rat, rabbit)
• Perkin Elmer IVIS Spectrium - Small Animal Optical (mouse, rat, rabbit)

Chicago

• Bruker 7T Clinoscan - Small Animal MRI (mouse, rat, rabbit)
• Mediso NanoScan PET/CT - Small Animal PET/CT (mouse, rat)
• Siemens 1.5 T Aera - Clinical Research HUMAN subjects
• Siemens 3 T Skyra - Clinical Research HUMAN subjects
• Siemns 3 T PET/MRI MMR - Clinical Research HUMAN subjects
• Siemens X-ray DSA - Small Animal X-ray (rat, rabbit)

Preclinical Validation of Polyvalent siRNA Gold Nanoparticle Conjugates as anti-Glioma Therapeutics

Glioblastoma multiforme (GBM) is a brain tumor with poor prognosis, despite treatment with surgery, radiation, and chemotherapy.  In a series of seminal studies that used both MR and optical imaging in the MTIC, Drs. Chad Mirkin (CAPS) and Alexander Stegh (TRIST) demonstrated that spherical nucleic acids (SNA), a technology developed in the Mirkin lab, can cross the blood-brain barrier (BBB), access tumor cells, and modulate the expression of known GBM oncogenes and tumor suppressors. This work showed that SNAs have a unique set of properties that are favorable for intracellular applications, such as their ability to enter cells in the absence of transfection agents, high binding coefficients for complementary DNA and RNA, nuclease resistance, minimal immune response, no observed toxicity, and highly effective gene regulating capabilities. A landmark paper demonstrated that Bcl2L12 -targeted SNAs showed efficacy in a xenograft model of GBM (Fig. 2).  Bcl2L12 is a potent caspase and p53 inhibitor that is overexpressed in the vast majority of human primary GBMs. To monitor distribution by MR imaging after intracranial or systemic administration, these SNAs were labeled with Gd(III) for fate mapping in vivo. Alternatively, labeling of these SNAs with Cy5.5 allowed their ability to traverse the BBB and to penetrate into the tumor cells to be monitored in vivo by near-infrared fluorescence (NIRF).  In a subsequent Genes and Developmentpaper, coauthored by TRIST program members C. David James, PhD, John Kessler, MD, and Marcus Peter, PhD, SNAs functionalized with mature miR-182 were administered intravenously and shown to reduce the tumor burden in glioma-bearing mice. miR-182 acts as a tumor suppressor by controlling the expression of Bcl2L12, c-Met, and hypoxia-inducible factor 2α.  The miR-182-SNAs penetrated the blood-brain barrier and disseminated through the tumors, inducing miR-182 expression, decreasing tumor burden (as shown by bioluminescence imaging of luciferase labeled 182-SNAs), and increasing animal survival. The Mouse Histology and Phenotyping Core and the Developmental Therapeutics Core also participated in this study. 

JensenSA *, Day ES *, Ko CH *, Hurley LA, Luciano JP, Kouri FM, Merkel TJ, Luthi AJ, Patel PC, Cutler JI, Daniel WL, Scott AW, Rotz MR, Meade TJ, Giljohann DJ, Mirkin CA and Stegh AH .Spherical Nucleic Acid Nanoparticle Conjugates as an RNAi - Based Therapy for Glioblastoma .Sci Transl Med . 5:209 ra 152, 2013. Supported by U54 CA151880, R01AR060810, R21AR062898, R01EB005866, and an American Cancer Society Research Scholar Award. Kouri FM, Hurley LA, Daniel WL, Day ES, Hua Y, Hao L, Peng CY, Merkel TJ, Queisser MA, Ritner C, Zhang H, James CD, Sznajder JI, Chin L, Giljohann DA, Kessler JA, Peter ME, Mirkin CA, Stegh AH .miR -182 integrates apoptosis, growth, and differentiation programs in glioblastoma . Genes Dev . 29:732-45, 2015. Supported by U54 CA151880, R01AR060810, R21AR062898 and an American Cancer Society Research Scholar Award.

MRI visible drug eluting magnetic microspheres for trans-catheter intra-arterial delivery to liver tumors

Hepatocellular carcinoma (HCC) patients are particularly vulnerable to the adverse effects of chemotherapeutic agents, including amonafide, an agent that forms a toxic metabolite and that can have severe side effects when administered systemically.  This problem can be overcome in the case of HCC, however, where local delivery to the tumor via the hepatic artery can be accomplished. In this study, conducted by Drs. Larson (CAPS) and  Kim (CAPS), MRI-visible amonafide-eluting alginate microspheres were developed for targeted arterial-infusion chemotherapy of hepatocellular carcinoma (HCC). A xenograft rodent model of HCC was used to demonstrate the feasibility of delivering these microspheres using hepatic transcatheter intra-arterial infusions and that delivery of these microspheres to both liver tumor and normal tissues could be visualized by MRI immediately after infusion (Fig. 3). This approach offers the potential for catheter-directed drug delivery to liver tumors and was a journal cover article.

Kim DH, Chen J, Omary R, Larson A. Theranostics 5:477-88, 2015. Supported by R01CA159178, R01CA141047, R21CA173491 and R21EB017986